Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability.

Background The factors influencing the severity of apnea‐related hypoxemia and bradycardia are incompletely characterized, especially in infants receiving noninvasive respiratory support. Objectives To identify the frequency and predictors of physiological instability (hypoxemia—oxygen saturation (SpO2) <80%, or bradycardia—heart rate (HR) < 100 bpm) following respiratory pauses in infants receiving noninvasive respiratory support. Methods Respiratory pause duration, derived from capsule pneumography, was measured in 30 preterm infants of gestation 30 (24‐32) weeks [median (interquartile range)] receiving noninvasive respiratory support and supplemental oxygen. For identified pauses of 5 to 29 seconds duration, we measured the magnitude and duration of SpO2 and HR reductions over a period starting at the pause onset and ending 60 seconds after resumption of breathing. Temporally clustered pauses (<60 seconds separation) were analyzed separately. The relative contribution of respiratory pauses to overall physiological instability was determined, and predictors of instability were sought in regression analysis, including demographic, clinical and situational variables as inputs. Results In total, 17 105 isolated and 9180 clustered pauses were identified. Hypoxemia and bradycardia were more likely after longer duration and temporally‐clustered pauses. However, the majority of such episodes occurred after 5 to 9 second pauses given their numerical preponderance, and short‐lived pauses made a substantial contribution to physiological instability overall. Birth gestation, hemoglobin concentration, form of respiratory support, caffeine treatment, respiratory pause duration and temporal clustering were identified as predictors of instability. Conclusions Brief respiratory pauses, especially when clustered, contribute substantially to hypoxemia and bradycardia in preterm infants.

ObjectiveTo evaluate the performance of a rapidly responsive adaptive algorithm (VDL1.1) for automated oxygen control in preterm infants with respiratory insufficiency.DesignInterventional cross-over study of a 24-hour period of automated oxygen control compared with aggregated data from two flanking periods of manual control (12 hours each).SettingNeonatal intensive care unit.ParticipantsPreterm infants receiving non-invasive respiratory support and supplemental oxygen; median birth gestation 27 weeks (IQR 26–28) and postnatal age 17 (12–23) days.InterventionAutomated oxygen titration with the VDL1.1 algorithm, with the incoming SpO2 signal derived from a standard oximetry probe, and the computed inspired oxygen concentration (FiO2) adjustments actuated by a motorised blender. The desired SpO2 range was 90%–94%, with bedside clinicians able to make corrective manual FiO2 adjustments at all times.Main outcome measuresTarget range (TR) time (SpO2 90%–94% or 90%–100% if in air), periods of SpO2 deviation, number of manual FiO2 adjustments and oxygen requirement were compared between automated and manual control periods.ResultsIn 60 cross-over studies in 35 infants, automated oxygen titration resulted in greater TR time (manual 58 (51–64)% vs automated 81 (72–85)%, p<0.001), less time at both extremes of oxygenation and considerably fewer prolonged hypoxaemic and hyperoxaemic episodes. The algorithm functioned effectively in every infant. Manual FiO2 adjustments were infrequent during automated control (0.11 adjustments/hour), and oxygen requirements were similar (manual 28 (25–32)% and automated 26 (24–32)%, p=0.13).ConclusionThe VDL1.1 algorithm was safe and effective in SpO2 targeting in preterm infants on non-invasive respiratory support.Trial registration numberACTRN12616000300471.

Mutations in the gene SLC19A3 result in thiamine metabolism dysfunction syndrome 2, also known as biotin-thiamine-responsive basal ganglia disease (BTBGD). This neurometabolic disease typically presents in early childhood with progressive neurodegeneration, including confusion, seizures, and dysphagia, advancing to coma and death. Treatment is possible via supplement of biotin and/or thiamine, with early treatment resulting in significant lifelong improvements. Here we report two siblings who received a refined diagnosis of BTBGD following whole-genome sequencing. Both children inherited compound heterozygous mutations from unaffected parents; a missense single-nucleotide variant (p.G23V) in the first transmembrane domain of the protein, and a 4808-bp deletion in exon 1 encompassing the 5′ UTR and minimal promoter region. This deletion is the smallest promoter deletion reported to date, further defining the minimal promoter region of SLC19A3. Unfortunately, one of the siblings died prior to diagnosis, but the other is showing significant improvement after commencement of therapy. This case demonstrates the power of whole-genome sequencing for the identification of structural variants and subsequent diagnosis of rare neurodevelopmental disorders.

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